1. Field of the Invention
This is invention is related to processes for synthesis of amphetamine derivatives and novel intermediates thereby.
2. Background of the Invention
The commercial importance of amphetamine derivatives has led to the development of numerous synthetic methods for their synthesis and their derivatization. One problem with amphetamine synthesis is that amphetamines have a stereo-defined amine center, which can be difficult to resolve and subject to racemization. Accordingly, for the preparation of a single stereoisomer, only stereospecific methods are useful. However, stereospecific methods do not provide the economic requirements of high yields, high selectivity and low process costs. Typically, the stereo center is purchased as part of a chiral starting material or utilize tedious and expensive synthetic reactions to achieve that goal. Such reactions involve a coupling agent, such as Grignard or organolithium reagents. Conventional teaching requires that the use such organometallics requires that the reaction temperature be maintained at a cold temperature, such as an ice bath at less than 10 degrees Celsius.
To complicate the amphetamine marketplace, there are established formulations which require racemic amphetamine to obtain an extended release of elevated blood levels of the drug. This racemic material can be obtained by mixing equal parts of the dextrorotary and levorotary stereos isomers or running a synthetic sequence which only produces racemic amphetamine.
Another problem with amphetamine synthesis is that the intermediates are toxic as well as flammable. This requires special handling such as double-walled drums and safety accommodations to protect manufacturing personnel.
The prior art in U.S. Pat. No. 6,399,828 teaches the production of amphetamine using various methods. In one approach norephedrine is refluxed with hydrogen iodide and red phosphorous. In another approach norephedrine is chlorinated using thionyl chloride and then catalytically hydrogenated. In U.S. Pat. No. 7,705,184, amphetamine synthesis is disclosed using hydrogenation of a chlorinated phenylpropanolamine. Aziridine chemistry, and specifically aziridine phosphoramidates are not taught in the amphetamine synthesis prior art.
Zwierzak et al. disclose a method of reacting N-phosphorylated aziridines with copper-modified Grignard reagents as a new route to substituted pyrrolines and pyrrolidines. However, Zwierzak et al discloses this method as being regiospecific, which it is not. Synthetic Communications: An Int'l J. for Rapid Commun. of Syn. Org. Chem., 28:7, 1127-1137 (1998).
Additionally, the use of protecting groups and leaving groups is well known. However, it has been discovered that there is significant variation among the various standard protecting groups. Specifically, where a carbonyl moiety is used as the amine protecting group (i.e. acetyl t-Boc or CBZ), the reaction must be kept at or below −10 degrees Celsius or the carbonyl will react with the organometallic reagent. Where a sulfonyl moiety is used as an amine protecting group (i.e. methanesulfonyl or p-toluenesulfonyl), it is difficult to remove the protecting group without destroying the molecule.
Accordingly, there is a need for synthetic processes and useful compounds for the manufacture of amphetamine and its derivatives that have high chemical yield, high selectivity, low cost, lower toxicity and are less dangerous to handle.